Renal cell carcinoma (RCC) is the sixth most common cancer in the U.S. afflicting 11,000 patients per year, and is one of the few cancers whose incidence is increasing. In light of the paucity of effective treatments and the frequency of late stage diagnosis, the 5-year survival of patients with metastatic RCC remains dismal. For the one-third of patients who present at the metastatic stage, there are several FDA-approved drugs available, among them the multi-kinase inhibitors and the mTOR inhibitors. Since progression-free survival even with these new drugs is only one to two years due to drug resistance, it is imperative that novel therapeutic approaches for patients with metastatic RCC be identified and validated. Sorafenib was the first FDA- approved targeted therapy for advanced RCC and works principally through its effect on VEGF and thus causes angiogenesis inhibition. Given that the vast majority of RCCs are associated with VHL mutations and are thus highly angiogenic, any means to augment the anti-angiogenic effects of existing drugs would be a major advance in the therapy of RCC. We have previously demonstrated a pronounced inhibitory effect of sorafenib's on the enzyme, soluble epoxide hydrolase (sEH), and our preliminary data show that the combination of sEH inhibitors with docosahexaenoic acid (DHA; a major component of fish oil) has synergistic anti-angiogenic effects in various cancers. For these reasons we hypothesize that sEH inhibition by sorafenib in the presence of fish-oil supplementation stabilizes epoxy docosapentaenoic acid (EDP; a metabolite of DHA) and thereby prevents RCC metastasis through modulation of tumor angiogenesis. In addition, we have evidence that fish-oil supplementation decreases the most prevalent and disabling adverse effect of sorafenib, systemic hypertension. Work in this project will demonstrate for the first time that the simple addition of fish oil to the FDA-approved drug sorafenib has great potential in the prevention and treatment of advanced kidney cancer.